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Review of EMEA Biosimilars Guideline

Last month EMEA (the European Medicines Agency) released final guidelines containing details of clinical, nonclinical and quality expectations for biosimilar protein therapeutics (aka generic biologics, aka biogenerics, aka follow-on biologics or proteins). These guidelines we're themselves as expansion of the general guideline released in September 2005 and of two earlier documents, a note for guidance containing nonclinical and clinical issues (December 2003) and a quality guideline (also December 2003). All of these documents are conveniently located on a single page on the EMEA website.

As of today, two biosimilar proteins have been recommended for approval by the CHMP (Committee for Human Medicinal Products, the human medicines technical componentwithin EMEA), both somatropins (growth hormones): Omnitrope (Sandoz) and Valtropin (BioPartners). Based on CHMP's specific guidelines for insulin and G-CSF biosimilars, we can infer that registration dossiers have been submitted for biosimilars in these categories (potentially adversely affecting primarily Novo Nordisk and Hoffman-La Roche, respectively). Other widely used therapeutic proteins that are susceptible to biosimilar competition in Europe today, owing to patent expiration, are erythropoeitin (Eprex, Janssen) and interferon-alpha2b (IntronA, Schering-Plough). We can expect CHMP guidelines for biosimilars for these drugs soon. In addition to Sandoz and BioPartners, companies that stand to gain in the near-term from the EMEA's actions are listed in this PharmaWeek article.

In the U.S., FDA has been considering it's own guidance for follow-on biologics (biosimilar) developers and manufacturers for some time. It's hinted that a draft guidance will be forthcoming this year. Sandoz isn't holding it's breath waiting for FDA to get it's act together on this issue. It sued FDA in September last year, asking the Court to rule that FDA must act on it's application for Omnitrope now, one way or another. FDA asked the Court to dismiss the suit in November. So far, no further action has occurred. In the meantime, U.S. observers can learn from the CHMP's guidelines, as it is likely that scientific guidance from FDA will be similar.

My goal in this issue is to provide an overview to these recent guidelines, focusing on the key issues. I'll discuss them in the order of general guideline, nonclinical, clinical and quality and then touch on the specific product guidelines. I realize that this is a long post, but it's far shorter than the original guideline documents, and it isn't every year that a completely new category of drug marketing authorization comes to fruition.

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results in products that are similar but not in generic equivalents, necessitating the need for clear product identification to facilitate pharmacovigilance.

Choice of reference product

Active substances must be similar (structure and function).

Reference product must be approved in the Community (meaning the countries embodied by the EMEA).

Pharmaceutical form, strength, and route should be the same; differences will have to be justified.

Note on immunologicals (e.g. vaccines)

Vaccines and allergens are complex and unlikely to be well characterized molecularly.

They will therefore consider them on a case-by-case basis.

Note on blood or plasma-derived products

Such products have complex and variable physico-chemical, biological and functional characteristics.

Therefore, such products must satisfy safety and efficacy requirements as found in BPWG "new products" guidance note and related documents.

Other biologicals

Cell and gene therapy products will be considered in the future.

My take away: Although the similar biological approach is potentially relevant to all biological medications, in fact, the current guidelines are intended primarily for development of biosimilars referenced to well-characterized recombinant protein therapeutics, including monocloncal antibodies.

Nonclinical Guideline

General (applicable to clinical as well)

Within a biosimilar MAA (marketing authorization application) dossier, each indication for use will be considered separately.

Efficacy and safety for each indication will either have to be demonstrated or an extrapolation from one indication to another justified.

Scope (applicable to clinical as well)

Covers biosimilar applications for recombinant proteins only and only when no changes are introduced in the manufacturing process.

Nonclinical study program

Studies should be done prior to clinical studies.

Should be designed to detect response differences between the reference and biosimilar, not just responses per se.

In vitro receptor-binding or cell-based [binding] assays should normally be done.

In vivo studies should measure the pharmacodynamics relevant to clinical use.

At least one repeat-dose toxicity study should be conducted.

Toxicokinetics should include antibody titers, cross reactivity and neutralizing capacity

Other routine types of tox studies are NOT normally required.

Clinical Guideline

General

Test product should be studied clinically using the final manufacturing process, unless justified and supported by additional data.

Clinical comparability is done in stages, much like a traditional program.

Pharmacokinetics

Clinical comparability pharmacokinetic (PK) studies should NOT necessarily mimic a standard comparability design that focuses on absorption and bioavailability. Rather, such studies should also include exploration of clearance and elimination.

Choice of design must be justified and careful attention should be paid to issues such as elimination half-life.

The acceptance range to conclude clinical comparability should be defined and justified.

Pharmacodynamics

The pharmacodynamic (PD) effects should be compared in a population where "possible differences can best be observed."

When will PK/PD studies alone suffice to determine clinical comparability:

when PK of the reference product is well characterized

when PD properties (e.g. binding to receptor) of the reference product are well characterized

when the PK/PD relationship of the reference is well characterized

when a PD marker exists and the PK/PD relationship using the marker is well known.

when the PD marker is a well characterized surrogate of the clinical outcome of interest

when the dose range is chosen to demonstrate assay sensitivity (see ICH E10 for a discussion of assay sensitivity)

when the PK and PD margins defining clinical comparability are defined and justified a priori.

Efficacy trials

Assay sensitivity must be ensured.

Clinical safety and pharmacovigilance

Safety data "should be obtained in a number of patients sufficient to address the adverse effect profiles of the test and the reference medicinal product."

Data from pre-approval studies are INSUFFICIENT to identify all differences in safety. Therefore, safety monitoring after approval is mandatory.

The pharmacovigilance plan must be approved prior to authorization and the systems must be in place to conduct monitoring when authorization is granted.

Applicant should identify in a risk specification possible safety issues resulting from a manufacturing process different from the originator.

Compliance with monitoring requirements will be closely monitored.

Immunogenicity

Immunogenicity must always be evaluated and the risk in different indications considered separately.

Data should be collected "from a sufficient number of patients to characterize the variability in antibody response" and antibody testing should be considered as part of all clinical trials.

The methods used to detect antibodies must be sufficiently sensitive to detect low-titer, low-affinity antibodies; standard methods should be used when possible.

Interference of antigen should be considered.

A different immune response between test and reference products requires investigation into the implications for clinical efficacy, safety and PK parameters of the test product.

Periodicity/timing of sampling should be justified.

Antibodies to process-related impurities should be considered.

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Quality Guideline

Introduction

EMEA recognizes that public-domain information is limited for the reference product. Nevertheless, they demand a level of detail in the comparison with the reference product "such that firm conclusions can be made."

A full quality dossier is required along with the demonstration of comparability.

Manufacturing Process

The applicant needs to demonstrate the consistency and robustness of it's process

Formulation studies "should be considered" to demonstrate the suitability of the formulation as regards stability, comparability, and integrity of active substance.

A separate (traditional) comparability exercise, as described in ICH Q5E, should be conducted whenever a change is introduced into the manufacturing process during development.

Comparability Exercise

Quality attributes will not be identical between test and reference products, but minor differences (e.g. post-translational modifications or impurity profile) should be justified.

Quality differences can impact the amount of nonclinical and clinical data needed.

Reference Product

Appropriate comparative tests at the level of the isolated active substance are generally needed, except in some cases when quality attributes of the active substance can be tested on the finished product.

The manufacturer should demonstrate that the active substance used in comparability studies is "representative of the active substance" present in the reference product.

Analytical Methods

Methods chosen must be able to detect "slight differences" in all relevant quality attributes.

Methods should be appropriately qualified as in ICH Q2(R1).

If standards and reference materials are available they should be used.

Physicochemical properties should be characterized, including post-translational forms.

Comparative biological assays should be conducted.

Impurities and stability of test and reference products should be compared.

Process-related impurities are expected, but their impact should be confirmed with appropriate studies.

Specifications

Specifications should be set as per standard practice for biological products, as defined by ICH Q6B.

Specification limits should be shown not to be wider than the range of variability of the reference product.

Individual Product Guidelines

Rather than provide details, which would make this post ridiculously long, I'll simply state that the individual guidelines provide some of the missing details from the above guidelines. Such details include, for example, the preferred design of PK/PD and clinical studies and recommendations for the scope of safety and immunogenicity evaluations. As it appears that CHMP intends to create guidelines for most, if not all, potential biosimilar products, biosimilar manufacturers would be advised to consult with CHMP formally prior to embarking on a biosimilar program. I would also advise them to seek additional specific guidance from the CHMP representatives who were/are primarily responsible for drafting the relevant biosimilar guideline. If possible, they should also contract with investigators who contributed to the development of the product guideline to aide with the design, conduct, and interpretation of the requisite comparability studies.

A couple of final thoughts. The EMEA has practically side-stepped some of the most difficult issuesthose pertaining to quality comparabilitywith these guidelines. As you can plainly see, the quality guideline provides few details for the steps biosimilar manufacturers need to take to meet the standards of quality comparability. The problem, of course, is that the reference product is made using a proprietary process with proprietary specifications and an active substance that might be impossible to isolate for the purpose of comparative studies. These difficulties haven't prevented two growth-hormone manufacturers from getting their biosimilar products approved in Europe. It would be of great interest to other manufacturers to learn the details of the quality and clinical programs that supported these marketing authorizations. Unfortunately, that information is proprietary too. We will have to await approval of Omnitrope in the U.S. for additional development details, albeit with redactions. When will an FDA scientific guidance be forthcoming? I'm guessing before the end of 2006.

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